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内容記述 |
Objectives: Fluoroform (HCF3) is used as a precursor for the synthesis of various CF3-containing compounds. In recent years, several studies have reported the reactivity of HCF3 and development of [11C/18F]HCF3 as radiolabeling agents [1-3]. However, the studies have remained some challenging issues, such as handling of precursor for radiolabeling agent and complexity of automated synthetic equipment. To solve these problems, we hypothesized that use of a difluorocarbene source would enable the synthesis of [18F]HCF3 using a two-pot automated synthesis system for [18F]fluoroalkylation reaction, like the use of BrCH2CH2OTf or glycidyl tosylate to produce gaseous [18F]FEtBr or [18F]EPIF. In this study, we developed a convenient method for synthesizing [18F]HCF3 via difluorocarbene produced in situ.Methods: The difluorocarbene source was determined for the difluoromethylation of 4-phenylphenol at 130 oC for 20 min in the presence of tBuOK. [18F]HCF3 was synthesized by the reaction of the optimal difluorocarbene source and [18F]KF/K2.2.2 in 1,2-dichlorobenzene at 130 oC for 2 min and immediately transferred by distillation into a reaction vial 2 containing benzophenone (1.5 mg) in DMF (500 L) and tBuOK, under an automated synthesis system developed in house. The [18F]trifluoromethylation of benzophenone was performed at 50 oC for 5 min as a model reaction. After the reaction, the reaction mixture was purified by the semi-preparative HPLC column.Results: To determine the optimal difluorocarbene source, the difluoromethylation of 4-phenylphenol as a model reaction was investigated. When ClCF2CO2Me, ClCF2CO2Na, and BrCF2CO2K were used and converted to difluorocarbene sources in situ, the difluoromethylated compounds were obtained in 13%, 3%, and 19% yields, respectively. Because BrCF2CO2K showed poor solubility in 1,2-dichrolobenzene, ClCF2CO2Me was selected as the optimal difluorocarbene source. The formation of [18F]HCF3 was confirmed by the reaction of ClCF2CO2Me and [18F]KF at 130 oC for 2 min without addition of proton source. As [18F]HCF3 has no significant UV signal, we performed a model reaction of [18F]HCF3 with benzophenone to determine the molar activity. The trifluoromethyl carbinol was obtained in 10 ± 2% radiochemical yield (isolated-yield based on the cyclotron-produced [18F]fluoride) and 0.61 ± 0.30 GBq/μmol molar activity. Reduction of the used amounts of ClCF2CO2Me and K2CO3 improved the molar activity to 12 GBq/μmol. Conclusions: We have successively synthesized [18F]HCF3 by applying the two-pot automated synthesis system for [18F]fluoroalkylation reaction and will continue to improve the molar activity of [18F]HCF3. In addition, this method is now applied to the synthesis of other CF3-containing radiolabeling agents |
